CAR-T细胞靶向整合膜蛋白减少小鼠模型脑部的原位胶质母细...

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技术资料下载地址: http://www.ncbi.nlm.nih.gov/pubmed/26822025

文献来源: Cancer Immunol Res.

CAR T cellstargeting podoplanin reduce orthotopic glioblastomas in mouse brains.

Abstract

Glioblastoma (GBM) is the most common and lethalprimary malignant brain tumor in adults with a 5-year overall survival rate ofless than 10%. Podoplanin (PDPN) is a type I transmembrane mucin-likeglycoprotein, expressed in the lymphatic endothelium. Several solid tumorsoverexpress PDPN, including the mesenchymal type of GBM, which has beenreported to present the worst prognosis among GBM subtypes. Chimeric antigenreceptor (CAR) transduced T cells can recognize predefined tumor surfaceantigens independent of major histocompatibility complex (MHC) restriction,which is often downregulated in gliomas. We constructed a lentiviral vectorexpressing a third generation CAR comprising a PDPN-specific antibody[NZ-1-based single chain variable fragment (scFv)] with CD28, 4-1BB, and CD3ζintracellular domains. CAR-transduced peripheral blood monocytes (PBMCs) wereimmunologically evaluated by calcein-mediated cytotoxic assay, ELISA, tumorsize, and overall survival. The generated CAR T cells were specific andeffective against PDPN-positive GBM cells in vitro. Systemic injection of the CART cells into an immunodeficient mouse model inhibited the growth ofintracranial glioma xenografts in vivo. CAR T cell therapy that targets PDPNwould be a promising adoptive immunotherapy to treat mesenchymal GBM.

CAR-T细胞靶向整合膜蛋白减少小鼠模型脑部的原位胶质母细胞瘤

摘要：

胶质母细胞瘤（GBM）是成人最常见的致死性原发性恶性脑肿瘤，5年生存率小于10%。Podoplanin（PDPN）是I型跨膜粘蛋白样蛋白，在淋巴管内皮细胞表面表达。有几种实体肿瘤过度表达PDPN，包括GBM间质型，而且是目前已报道的预后最差的GBM亚型。嵌合抗原受体（CAR）转导的T细胞可以识别肿瘤表面抗原独立的主要组织相容性复合体（MHC）的限制，这往往在胶质瘤表面是下调的。我们构建的慢病毒载体，三代CAR-T包括PDPN特异性抗体[ nz-1-为基础的单链可变区片段（scFv）与CD28和4-1BB，CD3ζ胞内域。CAR转导的外周血单核细胞通过钙黄绿素介导的细胞毒试验、ELISA、肿瘤大小、生存期和总生存期来进行免疫评价。CAR-T细胞特异性和体外抗GBM细胞积极有效。CAR-T细胞注射到免疫缺陷小鼠模型系统在体内抑制脑胶质瘤生长。CAR-T细胞治疗PDPN，将有希望过继免疫细胞治疗间质性GBM。

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